Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models (2009)

Introduction

Drugs such as cocaine, amphetamine, nicotine, alcohol, and marijuana are commonly used for their mood- and mind-altering properties. These substances also have the potential to be addictive. In some people, regular use leads to “addiction” or “dependence,” i.e., compulsive and repetitive drug-seeking behavior despite negative health and social consequences. However, this type of behavior does not occur in all users (see Fig. 1). Many people who experiment with drugs do not find the effects rewarding and avoid them in the future. Some people enjoy the effects of the drugs and use them recreationally without ever becoming dependent. For others, however, the drugs gain powerful control over their lives and may replace all other healthy pursuits (see Fig. 1). The majority of people who self-administer drugs of abuse begin during adolescence. Epidemiological studies have shown that earlier onset of drug intake is associated with greater likelihood of development of substance use problems. However, there is debate about whether early onset uniquely affects brain development in such a way as to promote pathological behavior or whether the same genetic and environmental factors that make an individual likely to develop drug problems also make them likely to initiate early. This review summarizes results from animal models in which the effect of age of onset has been examined.

Fig. 1

Percentages of the US population over the age of 12 years who have ever tried the indicated drug (top number, light gray circle); who used the indicated drug in the past month (middle number, darker gray circle); who meet criteria for dependence on the …

The terms “addiction,” “drug abuse,” and “drug dependence” are used interchangeably in the vernacular and have varying definitions in psychological, sociological, and neuroscience literature. For the sake of clarity, we will refer to the two substance use disorders (SUDs), drug dependence and drug abuse, as they are defined by the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV 1994).

For a diagnosis of drug abuse, a patient must present at least one of the following four characteristics:

1. Recurrent substance use resulting in the failure to fulfill major role obligations at work, school, or home
2. Recurrent substance use in situations in which it is physically hazardous
3. Recurrent substance-related legal problems
4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance

For a diagnosis of drug dependence, a patient must present three of the following seven characteristics:

1. Tolerance
2. Withdrawal
3. The substance is taken in larger amounts or over a longer period than was intended
4. There is a persistent desire or unsuccessful efforts to cut down or control substance use
5. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects
6. Important social, occupational, or recreational activities are given up or reduced because of substance use
7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance

Two of the criteria for drug dependence, withdrawal and tolerance, relate to physiological phenomena that ensue from repeated drug taking and are relatively easy to measure in animal models. New behavioral methods are approaching success at modeling increased intake, intake despite negative consequences, and the choice between drug intake and other activities, as described below.

The DSM-IV criteria provide a “snapshot” that clinicians can use when a patient requires diagnosis or treatment. However, drug dependence is actually a progressive disease, with several defined stages that often overlap with adolescence (Kreek et al. 2005; see Figs. 1 and and2).2). Drug dependence necessarily begins as experimental drug use; no person can become dependent without first taking a drug. Most people try drugs (at least alcohol or tobacco) at some point in their lives, typically experimenting during the late teenage years and early 20s (Chen and Kandel 1995). Some users repeat drug use under recreational circumstances. Recreational drug use can vary widely but is defined by the fact that the user has control over it. Recreational users seek drugs for their rewarding properties and not out of compulsion (Kalivas and Volkow 2005). Drug abuse and dependence begin to emerge when use becomes compulsive. The likelihood of progression from experimentation to recreational use to dependence varies by drug. Figure 1 provides a visual interpretation of this point by depicting the percentage of the population of the USA over age 12 that has ever taken a particular drug, uses regularly, or is dependent. Although the percentage that develops dependence varies by drug and is likely influenced by cultural and legal factors, the dependent population represents a small subset of those who have experimented with a drug. A key research question, therefore, is why do some drug users develop SUDs, while others can remain purely recreational?

Fig. 2

Stages in the progression to drug dependence (rectangles) and animal models related to each stage (ovals; self–admin, self-administration)

Epidemiological studies have provided insight into some factors that explain the difference between recreational users and those with SUD. One frequently observed correlation is that people who begin use at a young age are more likely to develop SUDs (Robins and Przybeck 1985; Meyer and Neale 1992; Lewinsohn et al. 1999; Prescott and Kendler 1999; DeWit et al. 2000; Lynskey et al. 2003; Brown et al. 2004; Patton et al. 2004) and tend to progress faster from experimentation to problem use (Chen and Kandel 1995; Chen et al. 1997). This correlation is the focus of the present review. Other contributing factors include family history of SUDs (Hoffmann and Su 1998; Hill et al. 2000) and psychopathology such as depression, anxiety, attention deficit disorder, schizophrenia, and conduct disorder (Deykin et al. 1987; Russell et al. 1994; Burke et al. 1994; Abraham and Fava 1999; Compton et al. 2000; Shaffer and Eber 2002; Costello et al. 2003). All of these factors are associated with increased risk of development of SUDs, but causality is difficult to address in human populations. In this review, we will examine attempts in animal models to address the question of whether drug taking at a young age is causal or merely coincidental in SUD development.

It is crucial at this point to define what we mean by “young.” Experimentation with alcohol, tobacco, and marijuana typically begins during the teenage years (SAMHSA 2008). Use of alcohol peaks around age 18–20 and declines into adulthood (Chen and Kandel 1995). Marijuana and tobacco use peaks slightly later, between ages 19 and 22 (Chen and Kandel 1995). Cocaine use peaks in the early to mid-20s and also declines into adulthood (Chen and Kandel 1995). The typical age-related pattern of drug use involves experimentation in the late teens and early 20s, so those who experiment before these typical times (alcohol and cigarettes in late childhood or the early teens or illegal drugs in the teens) are the most at risk. While many studies use an age of onset before 15 years as the cutoff for “early onset,” there is, in general, an inverse correlation: younger users are more likely to develop SUDs.

While the inverse correlation between age of onset and SUD liability is well established in humans, it does not tell us whether early use is causal. Epidemiological studies to test causality require twin or longitudinal studies which are difficult and rare. Two twin studies have resulted in conflicting results, albeit with different substances. One large study examining the risk for alcohol abuse and dependence reported that age of onset was correlated with but not causal in development of alcohol use disorders (Prescott and Kendler 1999). In contrast, a smaller study of twins who were discordant for early-onset marijuana use reported that age of onset was causal in development of later drug use and abuse problems (Lynskey et al. 2003). Thus, there is sparse evidence and lingering debate within the epidemiological literature regarding the causality of early-onset drug use as it relates to later drug problems. Human studies show that family history and psychopathology both increase the likelihood of early initiation (Tarter et al. 1999; Franken and Hendriks 2000; McGue et al. 2001a, b). Do these biological and environmental effects, therefore, operate through early initiation to increase vulnerability to SUDs? Or would users with a family history and/or psychopathology develop SUDs no matter when they initiate? These questions are difficult to address in human studies. To fully address the causality of early drug exposure on later SUD, animal models are necessary.

Animal models have the distinct advantage of experimental control. Experimenters can randomly assign the age of initial exposure, as well as the drug, dose, duration, and timing of exposure, whereas, in human studies, these conditions are determined by the user. For this reason, animal models have provided much valuable information. However, one drawback to animal use is that no model completely recapitulates the stages in development of SUD. For this reason, we must integrate results from multiple behavioral and neurobiological models to achieve a full understanding.

Early drug exposure

As shown in Fig. 2, the necessary first step toward development of drug dependence is drug intake. The quality of the first drug experience is crucial in determining future intake: for most drugs, people who enjoy their initial experiences are more likely to repeat drug intake (Haertzen et al. 1983). Drugs of abuse exert both rewarding and aversive effects (Wise et al. 1976), and the overall balance between these experiences during early drug use determines whether an individual will repeat drug taking in the future. In rodents, as described above, CPP, CPA, and CTA are used to assess initial reward and aversion and have provided valuable insight into the age dependence of such effects.

Rewarding effects

Some have speculated that elevated drug use in adolescence occurs because younger users find drugs more rewarding (Vastola et al. 2002; Belluzzi et al. 2004; Badanich et al. 2006; O’Dell 2009). There is some evidence that younger people and rodents derive greater reward from natural substances (Vaidya et al. 2004), which could generalize to addictive substances. If so, then younger users would likely take a drug more frequently or at higher doses, which could explain the faster progression to dependence seen in adolescents. Evidence to address this crucial question is mixed but indicates that adolescents are more sensitive to the rewarding effects of at least some drugs.

Nicotine is consistently more rewarding in adolescents (Vastola et al. 2002; Belluzzi et al. 2004; Torrella et al. 2004; Shram et al. 2006; Kota et al. 2007; Brielmaier et al. 2007; Torres et al. 2008). One study has shown that ethanol is more rewarding in adolescents (Philpot et al. 2003). Studies of psychostimulant reward (cocaine, amphetamine, methamphetamine) are more mixed but tend to indicate greater reward sensitivity in adolescents, particularly at lower doses (Badanich et al. 2006; Brenhouse and Andersen 2008; Brenhouse et al. 2008; Zakharova et al. 2008a, b; but see Aberg et al. 2007; Adriani and Laviola 2003; Balda et al. 2006; Campbell et al. 2000; Schramm-Sapyta et al. 2004; Torres et al. 2008). Tetrahydrocannabinol (THC) does not elicit strong conditioned place preferences in rodents. See Table 1. Overall, conditioned place preference studies suggest that adolescents are likely to find many drugs of abuse more rewarding, especially at threshold doses. More systematic dose–effect comparisons are needed in the literature.

Table 1

Age dependence of reward, aversion, self-administration, and withdrawal

Prolonged drug exposure

Role of pharmacokinetics in behavioral measures

Several pharmacokinetic properties of drugs of abuse could contribute to development of dependence. The rates of appearance and clearance of the drug in the brain (and at its molecular targets), the peak concentration, and the duration of exposure can affect the addictive effects of drugs (Sellers et al. 1989; de Wit et al. 1992; Gossop et al. 1992). Euphorigenic effects of drugs are enhanced by rapid accumulation in brain (de Wit et al. 1992; Abreu et al. 2001; Nelson et al. 2006). Although less studied, the aversive, reinforcing, and cognitive effects of drugs of abuse could be similarly affected by these pharmacokinetic variables. Rate of drug delivery is determined by the drug itself, the formulation, and the chosen route of administration. Studies comparing adult and adolescent pharmacokinetics of common drugs of abuse are sparse and not yet comprehensive with respect to dose, route of administration, and timing. The most informative studies have examined behavioral effects and pharmacokinetics in parallel and generally demonstrated that age differences in behavior are not related to varying drug levels.

Nicotine and its metabolite, cotinine, which may also be biologically active (Terry et al. 2005), are metabolized faster in adolescent than in adult rats (Slotkin 2002). However, in two studies in which nicotine dosing was adjusted to achieve comparable plasma levels, adolescents still exhibited reduced signs of withdrawal (O’Dell et al. 2006, b). Ethanol seems to enter the brain and blood at similar rates and extents in adolescents and adults (over a range of 5–30 min; Varlinskaya and Spear 2006) but it is cleared more rapidly from adolescent than from adult rodents, over a range of 2–18 h (Doremus et al. 2003). However, differences in sedation are not attributable to the difference in clearance. Little et al. (1996) showed that adolescent rats lose their righting reflex for a shorter duration than adults but, upon awakening, have higher blood alcohol levels. Similarly, age differences in locomotor sensitization to ethanol are independent of blood alcohol levels (Stevenson et al. 2008). Methamphetamine stimulates locomotor activity to a lesser extent in adolescent than adult mice despite achieving comparable brain concentration (Zombeck et al. 2009). For cocaine, one group has observed that adolescent mice have lower levels in blood and brain at 15 min postinjection than adults (McCarthy et al. 2004). In contrast, another group has shown higher levels at 5 min (Zombeck et al. 2009) despite observing reduced locomotor stimulation. Our group has measured equivalent levels in brain tissue and lower levels in blood in adolescents compared to adults despite the fact that we observed increased locomotor responses in adolescent rats (Caster et al. 2005). In summary, there are reports of differing pharmacokinetic profiles in adolescent vs. adult rodents, but they do not account for age-related behavioral differences.

Neurobiological considerations

The behavioral studies summarized above point to the conclusion that adolescents may tolerate higher and more frequent drug exposures, but there are not yet enough data to show whether they are more likely to develop compulsive patterns of drug taking and dependence-like behavior. Additional studies with more comprehensive models of drug dependence are necessary to confirm or refute this speculation. In addition, an understanding of the molecular and neurophysiological basis of drug dependence is key to determining whether the process happens more rapidly or extensively in adolescents. A large body of research is aimed at understanding the physiological basis of drug dependence. These findings have been extensively reviewed elsewhere (Robinson and Berridge 1993; 2000; Nestler 1994; Fitzgerald and Nestler 1995; Nestler et al. 1996; Volkow and Fowler 2000; Koob and Le Moal 2001; Hyman and Malenka 2001; Shalev et al. 2002; Winder et al. 2002; Goldstein and Volkow 2002; Kalivas and Volkow 2005; Yuferov et al. 2005; Grueter et al. 2007; Kalivas and O’Brien 2008). They provide a framework for evaluating molecular and neurophysiologic mechanisms that might mediate substance abuse vulnerability in adolescents.

Several studies have tested whether there are molecular and physiological differences between adolescents and adults that might underlie differential vulnerability to drug dependence (see (Schepis et al. 2008) for review). In general, molecular and physiological studies have revealed mechanisms that could be related to age differences in sensitivity to drug reward, but evidence about neuroplastic events related to the transition to compulsive drug use does not yet exist. The initial rewarding effects of drugs of abuse are dependent upon dopaminergic signaling. Adolescents have rapidly maturing dopaminergic neurocircuitry in the areas related to drug reward, in terms of presynaptic and postsynaptic function such as dopamine transporter and receptor expression (Seeman et al. 1987; Palacios et al. 1988; Teicher et al. 1995; Tarazi et al. 1998a, b, 1999; Meng et al. 1999; Montague et al. 1999; Andersen et al. 2002; Andersen 2003, 2005) and dopamine content in brain tissue (Andersen 2003, 2005). These studies have shown that innervation of the forebrain continues through adolescence, with levels of terminal markers such as dopamine content, transporters, and synthetic enzymes reaching a peak in late adolescence. Postsynaptic receptor number peaks and then declines to adult levels as innervation becomes complete. Most studies show that basal levels of synaptic dopamine are lower during this phase of development (Andersen and Gazzara 1993; Badanich et al. 2006; Laviola et al. 2001; but see Camarini et al. 2008; Cao et al. 2007b; Frantz et al. 2007) which is consistent with incomplete innervation. Adolescents also differ from adults in the amount of dopamine released in response to amphetamine and cocaine: the percentage change in extracellular dopamine level is greater in adolescents than adults (Laviola et al. 2001; Walker and Kuhn 2008; but see Badanich et al. 2006; Frantz et al. 2007), and the rate of increase may be faster in adolescents (Badanich et al. 2006; Camarini et al. 2008). In these studies, one critical determinant of the experimental results is the age at which the experiment was conducted: dopamine systems in early adolescence (day 28) are very different from those in late adolescence (day 42) and at the beginning of adulthood (day 60).

These neurobiologic differences between adolescents and adults are often not concordant with behavioral measures. For example, psychostimulant sensitization is reduced in adolescents despite greater increases in dopamine (Laviola et al. 2001; Frantz et al. 2007), while conditioned place preference is greater in adolescents despite comparable increases in dopamine (Badanich et al. 2006). One study that did observe concordance between dopamine release and intravenous self-administration reported no age difference in either measure (Frantz et al. 2007).

Similarly inconclusive findings have also been reported regarding the molecular and physiological responses to prolonged drug taking. Prolonged exposure leads to a decrease in the induction of immediate early genes (such as c-fos), upregulation of other genes, and the accumulation of long-lived proteins like delta Fos B, which persist for days or weeks (Kalivas and O’Brien 2008). These changes accompany and may mediate synaptic rearrangement in cortical circuitry and dysregulated glutamatergic signaling which are thought to underlie pathological drug seeking. A few studies have examined induction of c-fos in response to drugs of abuse in adolescents vs. adults, and the results are highly variable and dependent upon the brain region examined, stimulant used, and dose. Shram et al. observed that after low-dose (0.4 mg/kg) but not high-dose (0.8 mg/kg) nicotine, adolescents expressed greater c-fos in the medial nucleus accumbens shell (Shram et al. 2007a). Similar dose specificity of age effects has been reported for cocaine. Three studies have shown that adults generate more c-fos expression than adolescents in a few striatal subregions after high-dose (30–40 mg/kg) cocaine (Kosofsky et al. 1995; Cao et al. 2007b; Caster and Kuhn 2009). In contrast, adolescents have greater responses throughout the dorsal striatum and medial shell of the nucleus accumbens in response to lower-dose cocaine (10 mg/kg; Caster and Kuhn 2009). In many brain regions, however, fos induction is similar between the two ages (for nicotine amygdala, locus coeruleus, lateral septum, superior colliculus (Cao et al. 2007a; Shram et al. 2007a) and for cocaine bed nucleus of the stria terminalis (Cao et al. 2007b), cortex, and cerebellum (Kosofsky et al. 1995)). The stable protein product of the fos gene, delta Fos B, is also regulated in a drug- and region-specific manner. Upon treatment with nicotine, one group has reported no age effect (Soderstrom et al. 2007). After cocaine or amphetamine, adolescents express more delta Fos B in the nucleus accumbens and caudate putamen (Ehrlich et al. 2002). In general, the current studies are inconclusive about whether the molecular changes thought to be important for the transition to compulsive drug taking are exaggerated in adolescents.

The long-term behavioral effects of repeated drug taking are likely mediated by altered synaptic efficacy brought about by structural and biochemical mechanisms. Dendritic arbors in the nucleus accumbens and prefrontal cortex are altered after long-term cocaine and amphetamine exposure (Robinson and Kolb 2004), but these alterations have not yet been compared in adolescents vs. adults. After exposure to nicotine, dendritic length is differentially affected in adolescent vs. adult rats in the prelimbic cortex (Bergstrom et al. 2008) and nucleus accumbens (McDonald et al. 2007). The functional significance of these differences remains to be elucidated.

Electrophysiological responses can also be altered by drugs of abuse. For example, studies in adult rodents have shown that repeated self-administration or experimenter administration of cocaine reduces glutamatergic synaptic strength in the nucleus accumbens (Thomas et al. 2001; Schramm-Sapyta et al. 2005) and reduces long-term depression in the bed nucleus of the stria terminalis (Grueter et al. 2006). These alterations parallel altered expression levels of α-amino-3-hydroxyl-5-methyl-4-iso-xazole-propionate and N-methyl-D-aspartic acid receptors (Lu et al. 1997, 1999; Lu and Wolf 1999). Adolescent rats are generally more susceptible to plasticity in the nucleus accumbens (Schramm et al. 2002) and in many other brain regions (Kirkwood et al. 1995; Izumi and Zorumski 1995; Crair and Malenka 1995; Liao and Malinow 1996; Partridge et al. 2000) in response to electrical stimulation and could therefore be more susceptible to the effects of cocaine. The electrophysiological response of this circuit to drugs of abuse presents a potential mechanism for enhancing adolescent susceptibility to SUD but has not been directly compared in adolescent vs. adult animals. Many other potential mechanisms remain unexplored in adolescents vs. adults at this time, such as glutamate receptor expression (Lu et al. 1999; Lu and Wolf 1999) and chromatin remodeling (Kumar et al. 2005). If behavioral studies conclusively reveal that adolescent onset is causal in the progression to compulsive drug seeking, then these mechanisms should be explored.

Future studies should focus on linking molecular and physiological studies with relevant behavioral models to address which molecular alterations are most relevant to drug dependence and asking whether the currently identified differences between adolescents and adults might cause differences in behaviors related to SUD.

Summary

In this review, we have addressed the question of whether adolescents are more vulnerable to drug addiction than adults by summarizing results from animal studies. These studies suggest four conclusions:

1. The balance of rewarding vs. aversive effects of drugs of abuse is tipped toward reward in adolescents, as shown in place preference, place aversion, and taste aversion studies. This could increase consumption of drugs of abuse by adolescents.
2. Adolescents are consistently less sensitive to withdrawal effects. This could both promote drug use in early stages and protect against development of compulsive drug seeking after long-term use.
3. Adolescents are not consistently more sensitive to reinforcing or locomotor effects of drugs of abuse as shown in self-administration and sensitization studies.
4. Adolescents are undergoing changes in neuronal structure and function in brain areas related to reward and habit formation, which could influence susceptibility to drug dependence, although studies demonstrating causality are currently lacking.

These studies suggest that adolescents experience a different “balance” of rewarding and aversive effects of drugs of abuse. This balance could represent a potential vulnerability for increased experimentation. However, one critical element is missing in our ability to evaluate the risk of adolescent vulnerability to SUD. There are few data about the progression to compulsive drug seeking, the hallmark of drug dependence. It is imperative to more fully explore animal models of the progression to drug dependence to address whether adolescents develop compulsive use more frequently or rapidly than adults and whether adolescents are more or less resistant to extinction and reinstatement of drug taking. Second, more studies of the effects of adolescent exposure on cognitive function, particularly related to executive control, are warranted. Third, studies of molecular alterations in response to drugs of abuse in adolescents vs. adults are incomplete and inconclusive. As animal models of the progression to addiction become better understood and developed, molecular alterations underlying this transition can be explored in greater depth and the functional implications of these effects can be determined.

Finally, a key direction for future research is the intersection between age-related and individual differences. Human studies (Dawes et al. 2000) and some animal studies (Barr et al. 2004; Perry et al. 2007) suggest that genetics, environment, and psychopathology contribute to early drug taking and development of addiction. A better understanding of this relationship will greatly benefit prevention and treatment efforts: when we can determine who is most likely to become addicted and why, then we can prevent and treat drug problems in those individuals most successfully, regardless of when they initiate drug use.

Contributor Information

Nicole L. Schramm-Sapyta, Duke University, Durham, NC, USA.

Q. David Walker, Duke University, Durham, NC, USA.

Joseph M. Caster, Duke University, Durham, NC, USA.

Edward D. Levin, Duke University, Durham, NC, USA.

Cynthia M. Kuhn, Duke University, Durham, NC, USA.

References